Validation of Retinal Abeta as a Potential Biomarker of Alzheimer's Disease

验证视网膜 Abeta 作为阿尔茨海默病的潜在生物标志物

基本信息

批准号：
10431819
负责人：
Wellington Pham
金额：
$ 69.85万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10431819
关键词：
Address Aerosols Affinity Alzheimer disease detection Alzheimer&apos s Disease Alzheimer’s disease biomarker Amyloid beta-Protein Binding Biodistribution Biological Assay Blood Brain Cerebral cortex Cessation of life Chemicals Collaborations Community Health Curcumin Data Dementia Deposition Detection Disease Disease Progression Dose Drug Delivery Systems Early Diagnosis Early Intervention Elderly Excretory function Eye Fluorescence Formulation Foundations Goals Hippocampus (Brain)Image Inhalation Kinetics Lead Logic Memory Loss Metabolism Methods Modification Molecular Profiling Molecular Target Monitor Mus Nerve Degeneration Neurons Onset of illness Ophthalmology Pathology Patients Peptides Persons Pharmaceutical Chemistry Pharmaceutical Preparations Proteins Reporting Reproducibility Retina Safety Senile Plaques Signal Transduction Specificity Surrogate Markers Technology Testing Time Tissues Toxic effect Validation Work absorption aerosolized analog base chemical genetics cohort community setting cost early detection biomarkers early onset extracellular functional group high reward high risk improved in vivo in vivo evaluation in vivo imaging microscopic imaging molecular imaging neuron loss novel novel strategies potential biomarker professor response retinal imaging routine screening screening therapy outcome tool

项目摘要

PROJECT SUMMARY This application addresses the overarching challenge of detection of the early onset of β-amyloid plaques (Abeta) in Alzheimer's disease (AD). It does so by proposing a novel approach to image retinal Abeta by using signals emitted by curcumin fluorescence (FL). AD is the most common cause of dementia among elderly people. Its pathology is characterized by the presence of extracellular deposits of misfolded and aggregated Abeta peptides, which subsequently spread from the hippocampus to the cerebral cortex causing neuronal death and ultimately loss of memory, logic and the ability to speak. At present, no disease-modifying therapy is effective against AD nor it is possible to diagnose the early onset and/or the progress of the disease. Recent findings indicate that elevated levels of Abeta proteins are associated with dysfunctional neuronal networks both in the brain and eyes. Because AD undergoes a protracted asymptomatic stage before it reaches the advanced stage, a window of opportunity exists for early intervention, and successful detection of the early onset of the disease via routine screening will improve therapeutic outcomes and save lives. In that regard, early detection of Abeta in the eyes at ophthalmology centers, widely available in every health community settings seems ideal in terms of practicality, feasibility, safety and cost. Recently, our group demonstrated a novel approach for delivery of curcumin in vivo via inhalation of the curcumin aerosol. Further, in collaboration with Professor Joanne Matsubara, we recently demonstrated that inhaling curcumin aerosol resulted in significant accumulation of the compound in the retina. Further, we also demonstrated that curcumin binds to Abeta in retinal sublayers. Building on that foundation, we hypothesize that curcumin FL in the eyes can be used as a surrogate biomarker for assessing Abeta levels in the brain. Our long-term objective is to (i) demonstrate the newly synthesized curcumin analogs can be distributed and bind effectively to retinal Abeta; (ii) demonstrate retinal Abeta as a early biomarker of AD. A less well developed, but potentially powerful approach, marrying medicinal chemistry with drug delivery, and targeted molecular imaging, for high sensitivity molecular “fingerprinting” of AD in vivo, is the subject of this high risk-high reward proposal.

项目摘要该应用程序解决了检测早期β-淀粉样斑块的总体挑战（ABETA）在阿尔茨海默氏病（AD）中。它是通过提出一种新颖的方法来通过使用新颖的方法姜黄素荧光（FL）发出的信号。广告是较早的痴呆症的最常见原因人们。它的病理的特征是存在错误折叠和聚集的细胞外沉积物 Abeta肽，随后从海马散布到大脑皮质，引起神经元死亡，最终失去记忆，逻辑和说话能力。目前，尚无疾病改良疗法是对AD有效，也可以诊断疾病的早期和/或进展。最近的发现表明，Abeta蛋白水平升高与功能失调有关大脑和眼睛中的神经元网络。因为AD在前面发生了持久的无症状阶段它达到了高级阶段，存在一个机会窗口以进行早期干预，并成功检测通过常规筛查，疾病早期发作将改善治疗结果并挽救生命。在那考虑到眼睛中的Abeta的早期检测到眼科中心，在每个健康状况中都广泛使用在实践，可行性，安全性和成本方面，社区环境似乎是理想的选择。最近，我们的小组展示了一种通过吸入姜黄素在体内递送的新方法姜黄素气溶胶。此外，与乔安妮·马特斯巴拉（Joanne Matsubara）教授合作，我们最近证明了这一点吸入姜黄素气溶胶导致该化合物在视网膜中的显着积累。此外，我们也是如此证明姜黄素在残留的子层中与Abeta结合。在该基础的基础上，我们假设眼睛中的姜黄素FL可以用作评估大脑中Abeta水平的替代生物标志物。我们的长期目标是（i）证明新合成的姜黄素类似物可以分布并结合有效地进行视网膜Abeta；（ii）证明了残留的Abeta是AD的早期生物标志物。一种不太发达但潜在强大的方法，将医学化学与药物结合用于体内AD的高灵敏度分子“指纹”的递送和靶向分子成像是这个高风险高奖励提案的主题。